The clinical course of patients with chronic heart failure (HF) is usually stable…until it is not. This, of course, is a fanciful way of saying that the natural history of chronic HF varies considerably among patients and that it often changes abruptly over time. There has been increasing interest in identifying and studying episodes of worsening heart failure (WHF) that occur during the course of hospitalization for acute heart failure (AHF) (1). Yet even though symptomatic worsening occurs commonly in ambulatory patients, there has been surprisingly little attention paid to the significance of these events.

In this issue of JACC: Heart Failure, Mallick et al. (2) use data from the PROTECT (Pro-BNP Outpatient Tailored Chronic HF Therapy) study (3) to determine the incidence of WHF in ambulatory patients, factors that predispose to its occurrence, the relationship between WHF events and subsequent clinical course, and whether worsening can be prevented when management is guided by N-terminal pro–B-type natriuretic peptide (NT-proBNP) levels. In the PROTECT study 151 symptomatic patients with chronic HF with reduced ejection fraction (HFrEF) were randomly assigned to receive either standard of care (SOC) HF management or a goal to lower NT-proBNP concentrations ≤1,000 pg/ml in addition to SOC therapy. WHF was prospectively defined as: 1) new or progressive symptoms and/or signs of decompensated HF that 2) resulted in unplanned intensification of diuretic therapy.

The investigators found that over an average follow-up period of 10 months, 45 subjects (29.8%) developed WHF with a median time from enrollment to worsening of 128 days (range 6 to 521 days). Patients whose HF subsequently worsened were clearly already more congested at baseline, as evidenced by their significantly higher prevalence of jugular venous distention (51% vs. 29%) and edema (49% vs. 24%) and the trend toward a more frequent presence of pulmonary rales (18% vs. 10%) and an S3 gallop (36% vs. 25%). In general, patients who went on to develop WHF were less robustly treated with neurohormonal blocking agents at baseline and had lower estimated glomerular filtration rates and higher levels of biomarkers that predict risk (e.g., NT-proBNP, hsTnT, ST2, and Gal-3) than did patients whose condition remained stable during the observation period. Patients with WHF also had a significantly higher baseline EF (31% vs. 25%). The reason for this somewhat anomalous and counterintuitive finding is unclear. Although it may represent an artifact that reflects the small number of patients studied, it could be an indication that other structural or functional properties of the heart (e.g., diastolic function, secondary valvular regurgitation, pulmonary hypertension) play important roles in predisposing ambulatory patients with HFrEF to episodes of WHF. Regrettably, additional measures from the echocardiographic study that would have cast light on this issue are not provided.

WHF was associated with a less favorable clinical course. Patients who experienced an episode had a significantly higher subsequent likelihood of HF-related hospitalization or cardiovascular death than did patients without WHF (56% vs. 6%, p < 0.001). This difference was driven predominantly by HF-related hospitalization, which accounted for most of the events. There was a trend for NT-proBNP–guided care to reduce total WHF events, which occurred in 37% of patients in the SOC arm and 23% in the biomarker-guided arm of the study (hazard ratio: 0.50; p = 0.06). A secondary analysis using first incident WHF was significant in favor of the NT-proBNP–guided group compared with the SOC group (hazard ratio: 0.52; p = 0.04), and evidence indicated that guided care significantly improved the probability of survival without WHF.

The investigators are to be congratulated for focusing on WHF in ambulatory patients, a topic that has been largely neglected in the medical literature. Why that is the case is unclear because most clinicians recognize the variable clinical course of HF and know that episodes of worsening often auger the onset of a more troublesome future. Perhaps familiarity with WHF episodes in ambulatory patients with HF made this issue seem too obvious for the kind of scrutiny that Mallick et al. (2) have provided in this study. However, better recognition and understanding of the predictors and consequences of WHF are highly relevant and comprise a fertile topic for investigation. So, what have the results of this study told us, and where may we go from here in the future?

In the present study WHF was a potent predictor of HF-related hospitalization and cardiovascular death, an observation that supports using WHF as an inclusion criterion for clinical trials to enrich the study population with patients at increased risk of experiencing events that can be used to assess the efficacy of treatment. WHF may also serve as a potential endpoint for trials that assess the impact of various management strategies on the clinical course of patients with HF. For both cases, a standardized definition that is universally accepted and used across future trials would be helpful. Arriving at this point, however, is not as easy as it appears. A standard definition of WHF in patients hospitalized for AHF has yet to be determined. As a result, these events are defined differently in currently ongoing clinical trials in patients with AHF (4,5). Although the definition of WHF in ambulatory patients offered by the PROTECT investigators is a good start, in my view it requires greater precision before it can be more widely used. The requirement of only a single sign or symptom linked to an increase in diuretic therapy, although likely to be highly sensitive for detecting WHF, is not sufficiently specific, particularly for use as an endpoint of a trial. As currently written, either fatigue or weight gain fulfills the first part of the definition. Fatigue, however, is highly subjective and could be caused by numerous noncardiac conditions, whereas weight gain assumes that tissue weight is constant, a condition that becomes progressively less certain over time. Although unplanned intensification of decongestive therapy is a sensible component of the definition, there should be a threshold for increases that are considered clinically meaningful. The addition of a pre-defined increase of biomarkers such as NT-proBNP would also help increase specificity of the diagnosis.

The investigators provide information about the incidence of WHF and its time course. They also report that nearly 1 in 3 of the patients studied experienced 1 or more episodes of WHF over an average follow-up of slightly more than 4 months. This high prevalence of WHF, however, must be interpreted in the context of the population that was studied. The PROTECT study enrolled patients who were already at increased risk on the basis of the entry requirement of a previous HF-related hospitalization, and there was evidence of congestion in many of the patients at baseline. The finding that patients who were congested at baseline, were less robustly treated with neurohormonal blocking agents, and had worse renal function and biomarker evidence of more severe HF were more likely to experience worsening over a relatively short period of time is neither surprising nor helpful to clinicians. It is certain that both the incidence and the predictors of WHF in ambulatory patients will vary according to the baseline severity of HF and the population studied. Thus, information about the incidence, predictors, and consequences of developing WHF in different groups of patients (e.g., patients at lower risk, patients in more stable condition and less congested, and those with preserved EF) would be of particular interest. Hopefully publication of this report will stimulate the PROTECT investigators and others to pursue further studies to address these questions.

The observation that WHF in ambulatory patients is associated with a subsequent increase in events (predominantly HF-related hospitalization), although perhaps intuitive, is an important observation that indicates the need for enhanced follow-up surveillance and adjustment of therapies to prevent future events. This hypothesis, however, needs to be tested in appropriate cohorts of patients in future clinical trials. In addition, it is clear that worsening is not an all or none phenomenon. Information about the severity of WHF experienced by patients and patterns of changes in the signs and symptoms of HF over time (e.g., abrupt onset over hours or days compared with more insidious changes that gradually progress over weeks to months) as they relate to subsequent events would clearly be of value in helping clinicians better manage their patients with HF in the outpatient setting.

The present report also provides information indicating that the addition of NT-proBNP–guided therapy designed to achieve concentrations ≤1,000 pg/ml in addition to SOC therapy may result in a reduction in the incidence of WHF. These results add to the growing body of literature that biomarker-guided therapy may be of value in long-term patient management. However, the impact of guided therapy in preventing WHF episodes that was reported, although promising, is inconclusive in my opinion. In addition to the marginal level of significance and limitation posed by the relatively small number of patients and events, the report does not provide information about the baseline characteristics of the patients in the 2 treatment arms of the study. Such information is important to determine not only whether the populations were evenly matched at baseline for variables associated with increased risk for WHF events but also whether there were subsets of patients who may (or may not) have benefited from this strategy. In addition, we are not provided information about the success in achieving the desired and pre-defined goal of a reduction in NT-proBNP in the patients who were followed in the guided therapy arm. This information is critical for determining whether the strategy or some other factor was responsible for the favorable outcome with the guided treatment approach.

Like all good studies, the present one by Mallick et al. (2) raises more questions than it answers. That is not such a bad thing either, particularly for a topic such as WHF in ambulatory patients, which has been largely overlooked in the past. The study highlights the fact that the terms “common” and “obvious” may be discordant in that although episodes of WHF may be common, our understanding of the driving factors, indicators of risk, and consequences remains fragmentary and far from complete. The present study now places the topic of WHF in ambulatory patients directly in the “crosshairs,” and it is up to us where we take it in the future. There is clearly much to be learned and likely even more to be gained by further insights into these events.

Footnotes

↵∗ Editorials published in JACC: Heart Failure reflect the views of the author and do not necessarily represent the views of JACC: Heart Failure or the American College of Cardiology.

Dr. Greenberg has reported that he has no relationships relevant to the contents of this paper to disclose.